Present methods for synthesizing stereospecific aryl or alkyl substituted alkene or enone compounds, such as tamoxifen and tamoxifen analogs, suffer from problems such as relatively low overall yields, low specificity, lack of stereospecificity, and high cost of starting compounds.
GB patent 1,013,907 discloses the synthesis of alkene derivatives according to the formula R.sup.1 R.sup.2 N(CH.sub.2).sub.n O-.phi.-CR.sup.3 .dbd.CR.sup.4 R.sup.5 (".phi." hereinafter stands for phenyl), wherein R.sup.1 and R.sup.2 are C.sub.1-6 alkyl radicals; or wherein the --N--R.sup.1 --R.sup.2 group is a nitrogen-containing heterocyclic radical, where n is 2-6, R.sup.3 and R.sup.4 are aryl radicals, optionally substituted by one or more alkyl, alkoxy and/or dialkylamino-alkoxy radicals and/or one or more halogen atoms; and wherein R.sup.5 stands for an alkyl, alkenyl or aralkenyl radical. A process for synthesizing a compound according to the above formula is also disclosed including (1) dehydration of an alkanol derivative of formula R.sup.1 R.sup.2 N(CH.sub.2).sub.n O-.phi.-R, wherein R is CR.sup.3 (OH)CHR.sup.4 R.sup.5 or CHR.sup.3 C(OH)R.sup.4 R.sup.5.
Rebrovic and Koser, J. Org. Chem. 49:4700-4702 (1984) disclose that various terminal alkynes are found to react with (hydroxy(tosyloxy) iodo)benzene (HTIB) in CHCl.sub.3 to give either aryl (.beta.-(tosyloxy)vinyl) iodonium tosylates, or alkynylaryliodonium tosylates or a mixture thereof; however the HTIB is not disclosed, taught or suggested to function as a catalytic agent Miller and Al-Hassan, J. Org. Chem. 50:2121-2123 (1985) disclose a method for the stereospecific synthesis of (Z)-tamoxifen via carbomethylation of phenyl (trimethylsilyl) acetylene with diethylaluminum chloride-titanocene dichloride. However, such a synthetic scheme does not provide a commercially suitable method for synthesizing stereospecific tamoxifen for pharmaceutical preparation.
Coe and Scriven, J. Chem. Soc. Perkin Trans. 1:475-477 (1986) discloses the synthesis of tamoxifen by low valent titanium-mediated crossed coupling of substituted benzophenones according to the formula 4-R.phi.CO.phi., where .phi. is phenyl, R=MeO, ClCH.sub.2 CH.sub.2 O, BrCH.sub.2 CH.sub.2 O, CF.sub.3 C.sub.6 H.sub.4 O and Me.sub.2 NCH.sub.2 CH.sub.2 O, where the stereospecificity with propriophenone provides the corresponding but-1-enes, such as tamoxifen with 88% yield, but with a Z:E rating of 3:1, thus having only a 67% specificity for the desired Z stereoisomer.
Accordingly, there remains a need to overcome the above problems by providing a method for synthesizing stereospecific substituted enone and alkene compounds, such as tamoxifen or tamoxifen analogs, and particularly the Z form of tamoxifen and analogs thereof, in commercially suitable amounts, with a high degree of stereospecificity, e.g., greater than 70% or 80%, and in relatively high yield.